Heart failure affects ~3% of the adults and 37% of the Medicare population, and is the second leading cause for hospitalization within VA medical centers after psychiatric illness. A hallmark of patients suffering from chronic heart failure is dysautonomia, characterized by increased sympathetic tone and diminished parasympathetic tone. The importance of this autonomic imbalance is highlighted by the remarkable benefits in morbidity and mortality with the use of ?-adrenergic receptor blockers. In fact, all of our most effective pharmacological therapies to treat heart failure are targeted toward the efferent limbs of these aberrant neurohormonal pathways. However, no new proven effective drugs to treat heart failure have come forth in last couple of decades. How can we expand our therapies? We propose that targeting the triggers ? in particular the molecular receptors within the sensory neurons ? that initiate these pathological reflexes presents a novel strategy to abrogate the dysautonomia associated with heart failure. In fact, recent studies have shown that inhibiting the sensory pathways that trigger this dysautonomia can have beneficial effects on this autonomic imbalance, and improve cardiovascular function in animal models of heart failure. However, very little is known about these sensors at the molecular level. We and others have shown that acid-sensing ion channels (ASICs) are highly expressed in skeletal muscle and cardiac afferents, and within the carotid body, where they sense metabolic changes associated with ischemia and exercise, and initiate reflexes to maintain homeostasis. Accordingly, we have preliminary data demonstrating that ASICs are required for normal maximal exercise capacity in mice, and in Aim 1 we will define the mechanism by which ASICs contribute to exercise in health. However, these same sensory pathways are exaggerated in heart failure, and have been shown to contribute to the chronic associated dysautonomia. Thus, we hypothesize that ASICs are major contributors to this autonomic imbalance, and could serve as molecular targets to treat heart failure. Consistent with this hypothesis, our preliminary data indicate that ASICs in skeletal muscle afferents have altered biophysical properties in a mouse model of heart failure. Moreover, we have preliminary data showing that the deleterious cardiac remodeling that occurs after myocardial infarction is abrogated in ASIC knockout mice. The Aims of this proposal are to: 1) determine the mechanisms by which ASICs contribute to exercise physiology; and 2) determine the contribution of ASICs to the dysautonomia associated with heart failure. Understanding the beneficial role of ASICs during an acute stressor in health (exercise) is crucial to understanding their potential pathological role in a chronic stress condition (heart failure). Our studies will provide a better understanding of the molecular sensors that trigger dysautonomia, and could therefore lead to a novel means to treat heart failure, and possibly other chronic cardiovascular diseases.